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1.
Brain Sci ; 10(12)2020 Nov 24.
Article in English | MEDLINE | ID: mdl-33255421

ABSTRACT

BACKGROUND: Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID. METHODS: We used conditional Slc6a3DTR/+ mice to model progressive DA deficiency and the ß-adrenergic receptor (ß-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of ß-AR ligands on striatal ChIs. RESULTS: LID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that ß-ARs can effectively modulate ChI firing. CONCLUSIONS: The work suggests that pharmacological modulation of ChIs by ß-ARs might provide a therapeutic option for managing LID.

2.
Neuron ; 103(6): 1056-1072.e6, 2019 09 25.
Article in English | MEDLINE | ID: mdl-31324539

ABSTRACT

Motor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3DTR/+ diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs). Although the production and release of ACh and DA are reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase in striatal ACh relative to DA is heightened via D1-type DA receptors that activate ChIs in response to DA release from residual axons. These results suggest that stabilizing the expression of HCN channels may improve ACh-DA reciprocity and motor function in Parkinson's disease (PD). VIDEO ABSTRACT.


Subject(s)
Acetylcholine/metabolism , Cholinergic Neurons/metabolism , Dopamine/deficiency , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Interneurons/metabolism , Neostriatum/metabolism , Parkinson Disease/metabolism , Amphetamine/pharmacology , Animals , Cholinergic Neurons/drug effects , Cholinergic Neurons/physiology , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Dopamine/metabolism , Dopamine Agents/pharmacology , Dopamine Plasma Membrane Transport Proteins/genetics , Interneurons/drug effects , Interneurons/physiology , Mice , Neostriatum/cytology , Neostriatum/drug effects , Neostriatum/physiopathology , Parkinson Disease/physiopathology , Patch-Clamp Techniques , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Transcription, Genetic
3.
Neuroscientist ; 25(5): 475-490, 2019 10.
Article in English | MEDLINE | ID: mdl-30678530

ABSTRACT

The striatum is a critical component of the brain that controls motor, reward, and executive function. This ancient and phylogenetically conserved structure forms a central hub where rapid instinctive, reflexive movements and behaviors in response to sensory stimulation or the retrieval of emotional memory intersect with slower planned motor movements and rational behaviors. This review emphasizes two distinct pathways that begin in the thalamus and converge in the striatum to differentially affect movements, behaviors, and decision making. The convergence of excitatory glutamatergic activity from the thalamus and cortex, along with dopamine release in response to novel stimulation, provide the basis for motor learning, reward seeking, and habit formation. We outline how the rules derived through research on neural pathways may enhance the predictability of reflexive actions and rational responses studied in behavioral economics.


Subject(s)
Cerebral Cortex/physiology , Corpus Striatum/physiology , Decision Making/physiology , Neurons/physiology , Animals , Dopamine/physiology , Emotions/physiology , Glutamic Acid/physiology , Habits , Humans , Learning/physiology , Neural Pathways/physiology , Reward , Thalamus/physiology
4.
eNeuro ; 3(1)2016.
Article in English | MEDLINE | ID: mdl-26866057

ABSTRACT

Corticostriatal signaling participates in sensitized responses to drugs of abuse, where short-term increases in dopamine availability provoke persistent, yet reversible, changes in glutamate release. Prior studies in mice show that amphetamine withdrawal promotes a chronic presynaptic depression in glutamate release, whereas an amphetamine challenge reverses this depression by potentiating corticostriatal activity in direct pathway medium spiny neurons. This synaptic plasticity promotes corticostriatal activity and locomotor sensitization through upstream changes in the activity of tonically active cholinergic interneurons (ChIs). We used a model of operant drug-taking behaviors, in which mice self-administered amphetamine through an in-dwelling catheter. Mice acquired amphetamine self-administration under fixed and increasing schedules of reinforcement. Following a period of abstinence, we determined whether nicotinic acetylcholine receptors modified drug-seeking behavior and associated alterations in ChI firing and corticostriatal activity. Mice responding to conditioned reinforcement showed reduced ChI and corticostriatal activity ex vivo, which paradoxically increased following an amphetamine challenge. Nicotine, in a concentration that increases Ca(2+) influx and desensitizes α4ß2*-type nicotinic receptors, reduced amphetamine-seeking behaviors following abstinence and amphetamine-induced locomotor sensitization. Nicotine blocked the depression of ChI firing and corticostriatal activity and the potentiating response to an amphetamine challenge. Together, these results demonstrate that nicotine reduces reward-associated behaviors following repeated amphetamine and modifies the changes in ChIs firing and corticostriatal activity. By returning glutamatergic activity in amphetamine self-administering mice to a more stable and normalized state, nicotine limits the depression of striatal activity in withdrawal and the increase in activity following abstinence and a subsequent drug challenge.


Subject(s)
Amphetamine/administration & dosage , Central Nervous System Stimulants/administration & dosage , Corpus Striatum/drug effects , Drug-Seeking Behavior/physiology , Motor Cortex/drug effects , Neuronal Plasticity/drug effects , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Action Potentials/drug effects , Animals , Cholinergic Neurons/drug effects , Cholinergic Neurons/physiology , Conditioning, Operant , Corpus Striatum/physiology , Female , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Motor Cortex/physiology , Neural Pathways/drug effects , Neural Pathways/physiology , Receptors, Nicotinic/physiology , Reward , Self Administration , alpha7 Nicotinic Acetylcholine Receptor/physiology
5.
J Neurosci ; 33(25): 10405-26, 2013 Jun 19.
Article in English | MEDLINE | ID: mdl-23785153

ABSTRACT

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence.


Subject(s)
Acetylcholine/physiology , Adrenergic Uptake Inhibitors/pharmacology , Amphetamine/pharmacology , Glutamic Acid/physiology , Neostriatum/physiology , Neuronal Plasticity/physiology , Receptors, Presynaptic/physiology , Synapses/physiology , Animals , Choline O-Acetyltransferase/genetics , Choline O-Acetyltransferase/physiology , Dependovirus/genetics , Electrophysiological Phenomena , Excitatory Postsynaptic Potentials/genetics , Excitatory Postsynaptic Potentials/physiology , Genetic Vectors , Interneurons/physiology , Locomotion/physiology , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/physiology , Neostriatum/cytology , Neostriatum/drug effects , Neuronal Plasticity/drug effects , Postural Balance/physiology , Receptors, Dopamine D1/physiology , Receptors, Dopamine D2/physiology , Receptors, Presynaptic/drug effects , Synapses/drug effects
6.
Ann Neurol ; 73(3): 355-69, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23225132

ABSTRACT

OBJECTIVE: Prenatal cocaine exposure (PCE) can cause persistent neuropsychological and motor abnormalities in affected children, but the physiological consequences of PCE remain unclear. Conclusions drawn from clinical studies can sometimes be confounded by polysubstance abuse and nutritional deprivation. However, existing observations suggest that cocaine exposure in utero, as in adults, increases synaptic dopamine and promotes enduring dopamine-dependent plasticity at striatal synapses, altering behaviors and basal ganglia function. METHODS: We used a combination of behavioral measures, electrophysiology, optical imaging, and biochemical and electrochemical recordings to examine corticostriatal activity in adolescent mice exposed to cocaine in utero. RESULTS: We show that PCE caused abnormal dopamine-dependent behaviors, including heightened excitation following stress and blunted locomotor augmentation after repeated treatment with amphetamine. These abnormal behaviors were consistent with abnormal γ-aminobutyric acid (GABA) interneuron function, which promoted a reversible depression in corticostriatal activity. PCE hyperpolarized and reduced tonic GABA currents in both fast-spiking and persistent low-threshold spiking type GABA interneurons to increase tonic inhibition at GABAB receptors on presynaptic corticostriatal terminals. Although D2 receptors paradoxically increased glutamate release following PCE, normal corticostriatal modulation by dopamine was reestablished with a GABAA receptor antagonist. INTERPRETATION: The dynamic alterations at corticostriatal synapses that occur in response to PCE parallel the reported effects of repeated psychostimulants in mature animals, but differ in being specifically generated through GABAergic mechanisms. Our results indicate approaches that normalize GABA and D2 receptor-dependent synaptic plasticity may be useful for treating the behavioral effects of PCE and other developmental disorders that are generated through abnormal GABAergic signaling.


Subject(s)
Cerebral Cortex/pathology , Cocaine/toxicity , Corpus Striatum/pathology , Dopamine Uptake Inhibitors/toxicity , Neural Inhibition/drug effects , Prenatal Exposure Delayed Effects , Age Factors , Analysis of Variance , Anesthetics, Local/pharmacology , Animals , Biophysics , Dopamine/metabolism , Dopamine Agents/pharmacology , Drug Interactions , Electric Stimulation/adverse effects , Embryo, Mammalian , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Exploratory Behavior/drug effects , Female , GABA Agents/pharmacology , Green Fluorescent Proteins/genetics , Hindlimb Suspension/methods , In Vitro Techniques , Interneurons/drug effects , Interneurons/physiology , Lidocaine/analogs & derivatives , Lidocaine/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neural Inhibition/physiology , Neuronal Plasticity/drug effects , Patch-Clamp Techniques , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/physiopathology , Quinoxalines/pharmacology , Quinpirole/pharmacology , Receptors, GABA-A/metabolism , Rotarod Performance Test , Sodium Channel Blockers/pharmacology , Statistics, Nonparametric , Tetrodotoxin/pharmacology
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